The color of human skin is due primarily to the production of melanin by specialized cells in the skin called melanocytes through a process known as melanogenesis. The synthesis of melanin is a complex process involving several biochemical pathways. It is generally recognized that pigmentation may accompany inflammatory processes. Histamine is an agent involved in the inflammatory response which is reported to increase tyrosinase activity in human melanocytes, with the effects being completely inhibited by histamine antagonists such as famotidine. Histamine is postulated to induce melanogenesis in human cultured melanocytes by protein kinase A activation via H2 receptor. See Yoshida, M. et al., Journal of Investigative Dermatology (2000) 114, 334-342, the contents of which are incorporated by reference herein. Recently, the expression of histamine receptors on melanocyte cells has been reported. See Salim, S. et al., J Recept Signal Transduct Res. 2011 April; 31(2):121-31, the contents of which are incorporated by reference herein. However, the use of histamine antagonists to reduce pigmentation has received little attention to date.
Known depigmenting agents, such as hydroquinone and kojic acid, act as inhibitors of tyrosinase, an enzyme that has its catalytically active domain within organelles known as melanosomes. Tyrosinase converts phenols, including tyrosine, to ortho-quinones which are subsequently converted to melanin within the melanosomes. Other skin lighteners, such as plasminogen-activated receptor, act by disrupting the transfer of the melanosomes from melanocytes to the keratinocytes where melanin is deposited. While skin lighteners such as hydroquinone and kojic acid have found some utility in cosmetic and dermatological products, there remains a continuing need for products that effectively reduce pigmentation of skin particularly through mechanisms that may be complementary to those mentioned above to promote enhanced efficacy and/or synergies of combinations of depigmenting agents. It is therefore an object of the invention to provide compositions and methods for reducing pigmentation in human skin, including, for example, treatment of hyperpigmentation, unwanted pigmentation, age spots, liver spots, freckles, and the like.
The foregoing discussion is presented solely to provide a better understanding of nature of the problems confronting the art and should not be construed in any way as an admission as to prior art nor should the citation of any reference herein be construed as an admission that such reference constitutes “prior art” to the instant application.